title: Epigenetic reprogramming reverses the malignant epigenotype of the MMP/TIMP axis genes in tumor cells.
abstract: Cancer progression is characterized by extensive tumor invasion into the surrounding extracellular matrix (ECM) and migration to metastatic sites. The increased proteolytic degradation of the ECM during tumor invasion is directly dependent on the activity of matrix metalloproteinases (MMPs), counter-balanced by tissue inhibitors of matrix metalloproteinases (TIMPs). In this study, we found that unbalanced expression of MMP/TIMP axis genes in tumors was correlated with aberrant epigenotypes in the various gene promoters. The malignant epigenotypes could be therapeutically corrected by a simple defined factor-mediated reprogramming approach. Correction of the abnormal epigenotypes by nuclear remodeling leads to a rebalance in the gene expression profile, an alteration in tumor cell morphology, attenuation of tumor cell migration and invasion in vitro, and reduced tumorigenicity in nude mice. We further identified the downregulation of the MKK-p38 MAPK signal pathway as an important underlying mechanism for reduced tumorigenicity in this epigenetic reprogramming model. These data demonstrate that the malignant phenotypes seen in cancer can be corrected by a nuclear remodeling mechanism, thus highlighting a novel non-chemotherapeutic, non-radiotherapeutic approach for the treatment of cancer.
authors.affiliation: Division of Gastroenterology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China; VA Palo Alto Health Care System, Stanford University Medical School, Palo Alto, CA, 94304, USA.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Zhang
authors.forename: Bihui
authors.initials: B
authors.lastname: Zhong
authors.forename: Minhu
authors.initials: M
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Guanjun
authors.initials: G
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jiuwei
authors.initials: J
authors.lastname: Cui
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffman
authors.forename: Jifan
authors.initials: J
authors.lastname: Hu
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases
keywords: DNA methylation; MAPK signal pathway; TIMPs; cancer; cell reprogramming; epigenetics; epigenotype; histone modification; matrix; metalloproteinases